Here, we will determine if improved small molecules can protect the microtubule associated protein tau from a pathogenic cascade caused by the molecular chaperone Hsc70. Tau accumulates in traumatic brain injury (TBI), leading to neurodegeneration and cognitive deficits. Active Hsc70 binds to tau just after microtubule disruption precipitated by bast-induced axonal injury and then directs tau along one of two paths: It either preserves tau, even when it is hyper-phosphorylated, in an effort to recycle it to microtubules, or it triages au for a specialized degradation system called chaperone mediated autophagy (CMA). While this seems appropriate in principle, tau is actually a problem for CMA. It gets trapped in the channel called LAMP2a, and then it is cleaved into an aggregation-prone form that can seed further aggregation. So the mechanisms used by Hsc70 to triage tau are ineffective, and the overall outcome is its abnormal accumulation. We have shown that just by inhibiting Hsc70 with small molecules, tau is sent for proteasomal clearance, which is more effective for clearing tau than CMA. Therefore we predict that subverting tau away from CMA processing with Hsc70 inhibitors will reduce the pathogenic tau burden, and could possibly be a therapeutic strategy for TBI, especially immediately following blast TBI when tau fate is determined. We also predict that we will be able to use these small molecules to define the mechanism through which Hsc70 makes decisions about tau fate. Our team has developed an extensive suite of compounds that reduce tau levels in cells through this mechanism and a number of tools to investigate mechanism of action. Therefore, we will be able to evaluate both the efficacy of this approach for in vivo application whilealso dissecting the mechanisms involved in Hsc70 triage of tau. We have recently shown that Hsc70 inhibition by rhodacyanines can effectively lower tau in cells and in brain tissue. This scaffold has been modified to improve anti-tau potency and pharmacokinetics, even permitting BBB permeability. Thus, this compound family could hold promise as a viable drug candidate for tauopathies. We used this information to create a library of structurally diverse derivatives of the rhodacyanine backbone. But we do not know if they have improved neuronal anti-tau potency or pharmacokinetic profiles. We hypothesize that these properties can be improved. We propose a step-wise advancement process to test the potency, toxicity, efficacy and ADME/pharmacokinetic profiles of these derivatives. In addition to their potential therapeutic utility, the rhodacyanines provide excellent tool molecules to examine mechanisms of Hsc70-directed tau trafficking and turnover. We will also employ innovative cell-based assays, shRNA vector screening, and our developed compound toolbox to clarify how Hsc70 makes tau triage decisions and how they relate to its pathobiology. The proposed studies will hopefully form the foundation for a viable treatment approach in TBI.